When medicinal products are administered orally, the active substance is released in the gastrointestinal tract, and a proportion of the active substance is absorbed. By controlling the release of the active substance it is possible to influence the extent of absorption and the duration of action. Accordingly, various proposals have been made for controlling the release of the active substance by suitable galenical formulation of the active substance.
One approach is to provide dosage forms with coatings, so that the release of the active substance can be influenced in relation to the solubility or permeability of the coatings. Said coatings can for example be applied to tablets or capsules. In this case, however, there is the disadvantage that if the coating is defective or damaged, the release of the total dose of active substance may not be controlled in the desired manner.
An alternative is offered by multiparticulate dosage forms, in which the total amount of the active substance is distributed over a larger number of smaller units, such as pellets. If the individual pellets are provided with coatings, in the case of a defective coating on one pellet only a correspondingly small proportion of the total dose of active substance is not released in the desired manner.
A further advantage of these dosage forms based on pellets is that, after ingestion, sufficiently small pellets pass relatively quickly from the stomach into the intestine. In contrast, unless they disintegrate, tablets may remain in the stomach for quite a long time, and moreover the length of time varies considerably.
Despite the known advantages of pellets or multiparticulate dosage forms it is, however, difficult to obtain a desired release behavior. This is associated with the fact that, in the state of the art, it is difficult to prepare uniformly coated pellets. Even the pellet cores that are to be coated are of inadequate quality. In particular, pellets produced by extrusion are often of nonuniform shape and moreover have a rough and uneven surface, so that subsequent coating with film becomes difficult and it is scarcely possible to obtain films of good quality.
The films or coatings employed for controlling release can have various compositions. Thus, proposals have been made for controlling release in relation to pH value, time or bacterial enzymes that are present in the intestine.
With pH-controlled systems, however, there is the problem that the release of the active substance is altered by food intake, which has an effect on the pH value in the gastrointestinal tract. Moreover, there are considerable differences regarding pH values in the gastrointestinal tract between different individuals. Variability has also been reported in the case of controlled-release dosage forms controlled enzymatically.
Certain controlled-release dosage forms are therefore not completely satisfactory. There is the further problem that it is not possible to produce desired (specified) release profiles. Furthermore, the production of controlled-release dosage forms is often difficult. There is therefore a need for new controlled-release dosage forms as well as new methods for the production of controlled-release dosage forms.
The observations above apply in particular to dosage forms which contain a metoprolol salt, such as metoprolol succinate, for example. Metoprolol and its salts are cardio-selective beta blockers. They are used in the treatment of hypertension and also of a series of cardiovascular disorders. With disorders of this kind, a constant level of active substance in the blood is especially desirable. It is advantageous, furthermore, if preparations are made available that are suitable for a once-daily dosage. In this context a variety of dosage forms have been developed. They include tablets in which metoprolol is embedded in an insoluble matrix. In another preparation, coatings are applied to insoluble silicon dioxide cores. In terms of application and/or production, however, the stated dosage forms are not entirely satisfactory.